tbuckley/cabot-search huggingface dataset:
A phase I trial of androgen deprivation, darolutamide, and ipatasertib in a safety cohort with castration-resistant prostate cancer (ADDITION).
Authors: Sarah Elizabeth Fenton, Rachel Springsdorf, Siobhan Kenny, Lauren Bere, Ashley Ross, Masha Kocherginsky, Maha H. A. Hussain, David James VanderWeele
Journal: Journal of Clinical Oncology (2023)

174 Background: Alterations activating the PI3K-AKT pathway are found in 40-50% of patients with aggressive prostate cancer. This leads to an abrogated response to therapy with androgen-receptor (AR) pathway inhibitors (ARPIs) and is associated with poor outcomes. Preclinical in vivo models suggest there is synergy between ARPIs and AKT inhibitors. Methods: This is a single-arm study of the AR inhibitor darolutamide, the AKT inhibitor ipatasertib, and androgen deprivation therapy (ADT). The phase I safety cohort included patients with castration-resistant prostate cancer (CRPC). ADT was administered per institutional standards. Patients started with a lead-in of ipatasertib for 7 days, followed by ipatasertib combined with darolutamide 600 mg BID. The starting dose of ipatasertib was 400 mg daily with plans to de-escalate if ≥ 2 dose-limiting toxicities (DLTs) were identified in the first six patients. The DLT period was the first 4 weeks of combination therapy. The primary endpoint was to identify the recommended phase II dose (RP2D) of ipatasertib. A phase II biomarker-selected cohort was planned to receive the combination neoadjuvantly. That portion of the study was terminated prior to patient enrollment due to the withdrawal of industry support. Results: Six patients with metastatic CRPC were enrolled in the phase I cohort. They had received a median of 3 prior systemic therapies in addition to ADT (range 1-6). All patients completed the DLT period, and no DLTs were observed. The RP2D of ipatasertib, when given with darolutamide, is 400mg daily. Two patients (33%) had serious adverse events (SAEs) (diarrhea; grade 3) related to ipatasertib outside the DLT period. Two patients (33%) had SAEs unrelated to study drugs; pyelonephritis (one patient; grade 3) secondary to obstruction, and respiratory failure (one patient; grade 5) attributed to disease progression. Two (33%) patients had at least a 50% decline in PSA as the best PSA response, including 2 of 3 patients with known PI3K pathway alterations. Median PSA progression free survival (PFS) was 3.35 months (95% CI 3.06-NA). Median radiographic PFS was 2.91 months (95% CI 2.79-NA). Conclusions: Combination therapy with darolutamide and ipatasertib in CRPC is safe and a RP2D of ipatasertib was established. Toxicity was similar to the therapies given alone, and the most common treatment-related SAE was diarrhea. Partial response to combination therapy was seen in men with CRPC and known PI3K alterations. Clinical trial information: NCT04737109 .
Trial in progress: PRESTIGE—Primary retroperitoneal lymph node dissection (RPLND) for clinical stage II (CSII) testicular germ cell tumour (TGCT) and its impact on health-related quality of life (HRQoL) compared to chemotherapy or radiotherapy.
Authors: Ciara Conduit, Jeremy Howard Lewin, Elizabeth Chien Hern Liow, Haryana M. Dhillon, Wei Hong, Richard De Abreu Lourenço, Nathan Lawrentschuk, Benjamin Thomas, Peter S. Grimison, Nariman Ahmadi, Shomik Sengupta, Ben Tran
Journal: Journal of Clinical Oncology (2023)

TPS433 Background: As cure rates for patients with advanced TGCT improve, there is increasing focus on quality of survival. Increasingly, primary RPLND is being used as an alternative to chemotherapy (and radiotherapy) as primary treatment for selected individuals, due to the development of low morbidity surgical techniques (robot-assisted and extraperitoneal approaches), and recognition of acute and long-term toxicity of chemotherapy and radiotherapy. We hypothesise that primary RPLND compared to chemotherapy and radiotherapy will have less detrimental impact on HRQoL with comparable oncological outcomes. Methods: PRESTIGE is a prospective cohort study among adults with histologically confirmed advanced TGCT planned for primary RPLND, chemotherapy or radiotherapy. Eligible patients may have de novo advanced disease, or relapse within two- (NSGCT) or three-years (seminoma) following orchidectomy, without prior chemotherapy or radiotherapy (including adjuvant), and able to complete HRQoL questionnaires in English. See table for cohort-specific eligibility. Surgical approach (modality, template, adjuvant chemotherapy), chemotherapy regimen and radiotherapy dose will be administered at physician discretion and captured in Australia’s national multi-centre TGCT registry, iTestis, with clinical data in follow-up. Participants will complete HRQoL questionnaires focusing on physical, social, emotional, and functional domains commencing prior to treatment and continuing for 24 months. Questionnaires include EORTC QLQ-C30, EORTC QLQ-TC26, Brief Male Sexual Function Inventory and specific questions focusing on retrograde ejaculation and fertility. Patients undergoing RPLND will also have miR-371 evaluation pre-operatively and serially for 12 months after surgery. The primary outcome is change in EORTC QLQ-C30 global health status over 24 months for participants undergoing primary RPLND. Key secondary outcomes are changes in HRQoL, patterns of recurrence, surgical complications, retrograde ejaculation, and infertility. A sample size of 90 participants (30 for RPLND, 60 for chemotherapy) provides &gt;80% power to detect a mean difference of 28% in global health status at 0.05 significance favouring RPLND. Up to 30 individuals receiving radiotherapy may also be enrolled. The first site was activated 4-Aug-22; 2 of 3 study sites are active and 5 out of a planned 120 (4%) participants have enrolled. [Table: see text]
A cohort study evaluating the clinical, environmental and genetic profiles of men with early-onset, aggressive prostate cancer.
Authors: Sarah Elizabeth Fenton, Masha Kocherginsky, David James VanderWeele, Alicia K. Morgans, Phillip Lee Palmbos, Joshua J Meeks, James Benning, Siobhan Kenny, Brenda K. Martone, Brittany Szymaniak, Maha H. A. Hussain
Journal: Journal of Clinical Oncology (2023)

266 Background: The frequency of young men with aggressive prostate cancer (PC) at diagnosis is increasing. Clinical, environmental, and genetic drivers of this change have not been well characterized. Methods: This multi-institutional study evaluated two cohorts; Cohort 1 completed enrollment and is reported here. Eligible patients (pts) had early-onset (age ≤ 60 years) PC with metastasis (N+ or M+) at diagnosis, or within 5 years of curative intent local therapy. Data were collected to define clinical, environmental, and genetic profiles, including ctDNA and whole genome and transcriptome sequencing using Tempus xE. Standard descriptive statistics were used. Results: 46 pts were enrolled. Median age at diagnosis was 55 (range 41-60 years); 85% were White, 15% were Black; 4% served in the military and 4% reported biochemical exposure. 85% reported a family history of cancer, 46% had family history of PC. Median PSA at diagnosis was 19 (range 1-534 ng/mL), 56% had a Gleason score of 9-10, and 56% had de novo metastatic PC. 46% had prior local therapy. Genetic data is available for 40 pts. The most frequent clinically significant mutations (≥10% for somatic, ≥2.5% for germline) are summarized. 23 unique germline and over 1,000 unique somatic mutations were identified. Germline mutations associated with hereditary PC were found in 15%, all were associated with DNA damage repair (DDR). Somatic mutations in DDR genes were found in 10%. Co-mutations in TP53 and BRAF were seen in 30%. Interestingly, there were also incidental germline mutations identified that are associated with cardiac ( MYBPC, MYH7) and vascular ( MYH11, ACTA2) conditions, among others. Conclusions: In this cohort study we identified an unexpectedly high frequency of family histories that were positive for cancer (85%), and specifically PC (46%). However, rates of germline mutations associated with hereditary PC were similar to previous studies (15%), suggesting the possibility that other novel hereditary mutations driving increased PC risk may be present. Increased rates of somatic mutations in BRAF (35%) were also seen. The high frequency of BRAF mutations, particularly those that co-occur with TP53 mutations, may be driving more aggressive disease. We also found enrichment of mutations associated with non-cancer hereditary syndromes, including hypertrophic cardiomyopathy. These are not usually included in cancer-focused genetic studies, suggesting broader testing that includes potentially actionable incidental findings should be considered. More work is needed to define characteristics of this high-risk population and optimize management. [Table: see text]
TALAPRO-3: A phase 3, double-blind, randomized study of enzalutamide (ENZA) plus talazoparib (TALA) vs placebo plus ENZA in patients with DDR gene-mutated, metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Neeraj Agarwal, Fred Saad, Arun Azad, Joaquin Mateo, Nobuaki Matsubara, Neal D. Shore, Jayeta Chakrabarti, Hsiang-Chun Chen, Silvana Lanzalone, Alexander Niyazov, Karim Fizazi
Journal: Journal of Clinical Oncology (2023)

TPS279 Background: TALA is a poly(ADP-ribose) polymerase inhibitor (PARPi) that has shown efficacy in metastatic castration-resistant prostate cancers with alterations in DNA damage response (DDR) genes involved directly or indirectly in homologous recombination repair (HRR). ENZA is an androgen receptor (AR) inhibitor and established therapy for mCSPC. Since PARP activity has been shown to support AR function, PARP inhibition may increase sensitivity to AR-directed therapies. In addition, AR blockade downregulates HRR gene regulation, which has been hypothesized to induce a “ BRCAness” phenotype. These studies suggest that TALA in combination with ENZA may significantly improve clinical outcomes for men with mCSPC and DDR-HRR alterations. The phase 3, double-blind, randomized trial TALAPRO-3 (NCT04821622) herein presented will compare the combination of TALA plus ENZA vs placebo plus ENZA in this setting. Methods: Approximately 550 patients with mCSPC harboring DDR-HRR alterations will be randomized to TALA (0.5 mg once daily [QD]) plus ENZA (160 mg QD) or placebo (once daily) plus ENZA (160 mg QD). Patients will be stratified according to de novo mCSPC vs relapsed mCSPC, high-volume disease vs low-volume disease, where high-volume disease is defined as the presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis, and BRCA vs non-BRCA mutational status. Key eligibility criteria include age ≥18 years; histological diagnosis of prostate cancer; alterations in at least one of 12 DDR/HRR genes known to sensitize patients to PARPi ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C); and metastatic disease (no brain metastases). Primary endpoint is radiographic progression-free survival (defined as time to radiographic progression in soft tissue per Response Evaluation Criteria in Solid Tumors version 1.1 or in bone per Prostate Cancer Working Group 3 criteria by investigator, or death). Secondary endpoints include overall survival, safety, and patient-reported outcomes. Patient recruitment is planned/ongoing at approximately 285 sites in 27 countries, including the US and Europe, South America, South Africa, and Asia-Pacific. As of 30 September 2022, a total of 319 patients have been randomized in the study. This study was approved by an Institutional Review Board. Clinical trial information: NCT04821622 .
Limited relevance of the “very low risk” prostate cancer classification in the modern era: Results from a large institutional active surveillance cohort.
Authors: Kevin Shee, Janet E. Cowan, Samuel L. Washington, Hao G Nguyen, Katsuto Shinohara, Peter Carroll, Matthew R. Cooperberg
Journal: Journal of Clinical Oncology (2023)

381 Background: Although the American Urological Association recently dropped the “very low risk” (VLR) category for prostate cancer (PCa), the National Comprehensive Cancer Network (NCCN) guidelines still maintain this stratum based on number of positive biopsy cores, tumor extent in each core, and PSA density. This subdivision may be outdated in the modern era in which targeted prostate biopsies are common practice. We identified the proportion of VLR patients at our institution to determine whether an alternative classification may be more appropriate for risk-stratification in the modern era. Methods: Participants were diagnosed from 2000-2019 with cT1-2N0/xM0/x PCa, PSA &lt;20ng/ml, biopsy Gleason grade group (GG) 1-2, and initially managed with AS. VLR PCa was defined as &lt;3 positive cores, ≤50% cancer per core, and PSA density &lt;0.15. UCSF-CAPRA score was calculated for each patient. The primary outcome was major upgrade (≥GG3) on subsequent biopsy. Multivariable Cox proportional hazards regression models were used to calculate associations between CAPRA score and risk of major upgrade, adjusting for age, genomic testing, and prostate MRI finding. Results: Of 1554 patients initially managed with AS, 364 (23%) met NCCN VLR criteria. 49 (3%), 781 (50%), 505 (33%), and 219 (14%) patients had CAPRA scores of 0, 1, 2, and 3, respectively. Proportion of patients deemed VLR decreased over time; among 84 patients initially managed with AS during or after 2018, only one patient (1%) met VLR criteria in 2018, while the stratification by CAPRA demonstrated that 21 (25%), 25 (30%), and 38 (45%) patients had CAPRA scores of 1, 2, and 3, respectively, over the same period. CAPRA score was significantly associated with major upgrade on biopsy on multivariable Cox proportional hazards regression modeling independent of age, genomic testing, and MRI finding (HR 1.46, 95%CI 1.22-1.74, p&lt;0.01). Conclusions: The relevance of VLR PCa in the modern targeted biopsy era has diminished, with no cases meeting VLR criteria in a large AS cohort after 2018. CAPRA score is an option for a more contemporary risk stratification tool for men on AS.
Characteristics of long-term responder (LTR) patients (pts) treated with androgen-receptor signaling inhibitors (ARSI) as a first-line treatment for metastatic castration-resistant prostate cancer (mCRPC): Real-world evidence from four high-volume institutions.
Authors: Orazio Caffo, Consuelo Buttigliero, Carlo Cattrini, Davide Bimbatti, Massimiliano Cani, Nicolò Cavasin, Veronica Crespi, Giovanni Farinea, Dzenete Kadrija, Stefania Kinspergher, Eleonora Lai, Francesca Maines, Alessia Mennitto, Antonello Veccia, Giovanni L. Pappagallo, Marco Maruzzo
Journal: Journal of Clinical Oncology (2023)

164 Background: ARSI [enzalutamide (ENZA) and abiraterone (ABI)] demonstrated to be efficacious as a first-line therapy for mCRPC, showing a median progression-free survival of 16 and 20 months (mos) in pivotal trials, respectively. Nevertheless, some pts of daily clinical practice show exceptionally prolonged disease control with very long duration of treatment. The present study aimed at identifying the characteristics of LTR pts who received one ARSI as a first-line for mCRPC. Methods: We retrospectively reviewed the clinical records of a consecutive series of 647 pts treated in the daily clinical practice with one ARSI as first-line mCRPC in four Italian high-volume Institutions. Pts who had previously received docetaxel in castration-sensitive setting were excluded. Pts received standard AA or ENZA doses (1,000 mg po daily plus prednisone 10 mg po daily or 160 mg po daily, respectively). ARSI were administered until progression and were followed according to each Institution policy. For each pt we recorded pre and post-ARSI clinical history, baseline characteristics, treatment details and clinical outcomes. Pts were considered as LTR in presence of an ARSI exposure ≥ 36 mos. LTR were compared to the progressed pts with an ARSI exposure &lt; 36 mos. On-treatment pts with an ARSI exposure &lt; 36 mos were not considered. Results: We identified 81 LTR pts (53 treated with ENZA and 28 treated with ABI). The median age was 76 yrs (range 56-89). The median treatment duration was 46.1 mos (range 36.4-88.6) and 52 pts were still on treatment. LTR were compared to no-LTR 415 pts (233 treated with ENZA and 182 treated with ABI). Compared to no-LTR, LTR pts showed longer PSA doubling time (PSADT) (PSADT) (p = 0.001) and time to mCRPC (p &lt; 0.0001), lower levels of basal PSA (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01), better ECOG PS (p = 0.01), lower Gleason score (p = 0.01), and less pain level (p = 0.04). ECOG PS, ALP, time to mCRPC and PSADT were all identified as independent predictors of time to treatment interruption in multivariate analysis. LTR showed an 89% decreased risk of death compared to no-LTR (HR = 0.11 IC95% 0.06-0.18). Conclusions: In our experience, several variables, which are usually considered as having a prognostic value, demonstrated to be able to predict the probability of prolonged disease control in mCRPC pts treated with first-line ARSI.
The Bristol Bladder Trial: Five year outcomes in patients treated with neoadjuvant cabazitaxel and cisplatin chemotherapy for muscle invasive transitional cell carcinoma of the urinary bladder.
Authors: Amarnath Challapalli, Paul White, Susan Masson, Emily Foulstone, Emily Renninson, Alicia Bravo, Sylvia Pearson, Narges Dailami, Raj Persad, Anthony Koupparis, Edward Rowe, Jon Oxley, Julian Kabala, Janice Ash-Miles, Amit Bahl
Journal: Journal of Clinical Oncology (2023)

493 Background: Neoadjuvant cisplatin-based combination chemotherapy (NAC) improves survival in muscle invasive bladder cancer (MIBC). However, response rates and survival remain suboptimal. We sought to evaluate the efficacy of cabazitaxel with cisplatin in this patient group. These patients have now been followed for survival status for 5 years post NAC and radical cystectomy. Methods: This was a single arm (Simon 2 stage), phase 2 study. Patients with MIBC were included if fit to receive NAC and to undergo radical cystectomy. 26 evaluable patients were required to detect an objective response rate (ORR) of &gt;35% with 80% power. ORR was defined as pathological complete response (pCR) plus partial response (pathological downstaging, ≥T2 at diagnosis to ≤T1 at cystectomy). Treatment was with cisplatin 70mg/m 2 and cabazitaxel 15mg/m 2 on day 1 of a 21-day cycle, for 4 cycles prior to surgery. Toxicity was recorded using CTCAE v.4.03. QoL data was assessed during and after chemotherapy using EQ-5D-5L and EORTC-QLQ-C30, BLM30 questionnaires. Patients were followed for 5 years post cystectomy for progression free survival (PFS) and overall survival (OS). Results: ORR was seen in 15 out of 26 evaluable patients, 57.7%, with 24.6% achieving pCR. 1 out of 15 patients who achieved ORR died due to disease progression in the 5 year follow up period. The median PFS and OS were not reached by the 5 year follow up time point with a 5 year survival rate of 65.4% being seen in this patient cohort. Median OS in non-responders (11 patients) was 20.5 months and 5 year survival rate for the non-responders was 36.4% compared to 93.3% for responders. Conclusions: Neoadjuvant cabazitaxel with cisplatin chemotherapy is an effective regimen with 65.4% patients alive and progression-free at 5 years. It also indicates that ORR (and not just pCR), is a good predictor of patient survival at 5 years post radical cystectomy with only 1 out of 15 patients who achieved ORR progressing and dying in this period. However, in current clinical practice, there are no validated predictive biomarkers regarding potential response to NAC. Taken together with our previously published data, cabazitaxel with cisplatin as neoadjuvant chemotherapy is a safe, well-tolerated and effective regimen and should be compared to the regimens e.g. cisplatin/gemcitabine considered as standard in this setting. Clinical trial information: NCT01616875 .
A real-world registry of patients with metastatic castration-resistant prostate cancer (mCRPC): REMPRO study.
Authors: Francisco Gonzalez, Rohit Kodagali, Teresa Tung, Mohamed Masoud, Viraj Rajadhyaksha
Journal: Journal of Clinical Oncology (2023)

TPS286 Background: Rapidly expanding treatment armamentarium for mCRPC calls for an appropriate patient and treatment selection, and sequencing with existing agents. Data describing mCRPC management are fragmented across Africa, Asia Pacific, Latin America, and the Middle East with marked cross-country differences in treatment practices and patient outcomes. To address these gaps, we have established an mCRPC registry (REMPRO) that aims to describe the real-life treatment patterns and their associated survival outcomes in patients with mCRPC in non-US and non-European region. The results of this study may serve as baseline data for the policy makers in devising access programs for novel therapies in this region. Methods: REMPRO is an ongoing multinational, multicenter, retrospective, non-interventional real-world cohort study in adults diagnosed with histologically or radiologically confirmed mCRPC between 01 January 2016 and 31 December 2018 who have progressed on androgen deprivation therapy alone and received at least one line of treatment in routine clinical care, with at least 12 months of available records. After obtaining informed consent, clinical information from medical records (from index date [mCRPC diagnosis] to end of follow-up [until death, last record entry or date of data extraction]) is captured into electronic system. Data collection includes demographics, clinico-pathological characteristics, disease status, treatments received, outcomes, laboratory results, comorbidities, and healthcare resource utilization. Primary outcome analysis will describe real-world treatment patterns (monotherapy or as combinations) for overall cohort, each country, and in pre-defined subgroups like castration sensitivity, ECOG performance, AJCC staging, Gleason grade and/or score, site of metastases, and genetic alterations ( BRCA1/BRCA2 and/or HRRm). Secondary outcome analysis will include overall and real-world progression-free survival associated with different treatment regimens using Kaplan–Meier method. Of the planned sample size of 991 patients, a total of 760 patients with mCRPC have been enrolled until 26 August 2022 from 34 oncology centers across 8 countries (Colombia: 51, Egypt: 83, India: 200, Peru: 32, Saudi Arabia: 16, South Korea: 300, Turkey: 53, UAE: 25). Analysis of the dataset for primary and secondary endpoints have not been performed. Clinical trial information: NCT04801186 .